Impact of gender on the long-term outcome and survival of patients with autoimmune hepatitis☆
Introduction
Autoimmune hepatitis (AIH) is a disease of the hepatic parenchyma characterised by progressive inflammatory destruction. It is associated with a female preponderance, the presence of circulating autoantibodies, hypergammaglobulinaemia, interface hepatitis on liver biopsy, and it typically responds to immunosuppressive therapy [1].
The observed female gender bias is consistent with many other autoimmune diseases where there is likewise an increased susceptibility in women. Although the reasons behind this are unclear, it is well established that hormones and the hypothalamic–pituitary–gonadal system may modulate the immune response [2], [3], [4], [5], [6], [7], [8], [9], [10]. Physiological examples include amelioration of disease activity during pregnancy in patients with multiple sclerosis (MS) and rheumatoid arthritis (RA) [9], [10]. In patients with AIH, amelioration of disease activity from the second trimester of pregnancy, followed by post-partum flares, has been demonstrated in two series [11], [12]. In one of these series, disease exacerbation during pregnancy was also demonstrated, albeit in only 4/35 (11.4%) pregnancies [12].
Given the alteration of disease behaviour in conditions such as MS and RA under different hormonal environments, it might also be expected that disease expression and clinical outcome differ according to gender. Indeed, male patients with MS demonstrate more severe disease with an increased rate of cerebellar involvement, higher rates of primary progressive disease and require assisted walking devices after a shorter time period than women [13]. Conversely in RA, disease activity is more severe and long-term outcome poorer in female patients although male patients are more likely to die from extra articular manifestations of the disease [14].
To date, there has been little described pertaining to the influence of gender on the course and outcome of AIH. A report by Czaja et al. [15] investigated outcomes in a large US tertiary referral centre and found no differences in clinical outcome between 144 women and 41 men with AIH, although an increased frequency of concurrent autoimmune diseases and an increased prevalence of human leucocyte antigen (HLA) DR4 in female patients compared to male patients were noted [15].
In view of the paucity of existing data regarding the influence of gender on patients with definite AIH, we have investigated factors affecting susceptibility to the disease, presentation, severity of illness and outcome between men and women who fulfilled diagnostic criteria for definite AIH in a European setting.
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Methods
The medical records of 238 patients (51 male, 187 female) with a diagnosis of definite AIH, median International AIH Group (IAIHG) [1], [16] score 22 (range 16–28), who presented between 1971 and 2005 at King’s College Hospital (KCH) were examined from a prospectively obtained database. The influence of gender on presentation, clinical course, response to therapy, incidence of hepatocellular carcinoma and clinical outcome (time to either death or liver transplantation (LT)) was evaluated.
Patient demographics and laboratory parameters at presentation
The female to male ratio was approximately 4:1 in our patient cohort. Both groups of patients were followed for a similar length of time (median 14 years, range 1–35 y for males vs. 11 y, range 0.1–30 y for females, p = 0.0773) (Table 1). Female patients tended to be older at presentation (median age 39 y for males vs. 49 y for females, p = 0.0589). The age distribution for men and women is illustrated in Fig. 1. There were no statistically significant differences between the two groups with regard to
Discussion
This large, single, tertiary centre study provided the opportunity to undertake a comprehensive analysis of the influence of gender on outcomes and disease severity in AIH. The most striking difference demonstrated in this study was that men with AIH appeared to have better long-term survival and outcome than their female counterparts. Furthermore, expression of HLA A1, B8, DR3 allotypes and the HLA A1–B8–DR3 haplotype was all increased in male patients compared to female patients. Men with AIH
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The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.